P2–014: Presenilin mutations impair mitochondrial dynamics in neurons

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in selective brain regions. Mitochondrial dysfunction is a prominent and early feature of the disease, although the underlying mechanism is still not clear. Mitochondria are dynamics organelles that undergo continual fission and fusion events which serve crucial physiological function. Our recent studies demonstrated that an altered balance in mitochondrial fission and fusion was likely an important mechanism leading to mitochondrial and synaptic/neuronal dysfunction in AD brain. Mutations in presenilins (PS) cause early-onset familial form of AD (fAD). PS1 is found in mitochondria and mutant PS1 affects mitochondrial function and transport, suggesting that PS1 mutants may cause mitochondrial/neuronal dysfunction through regulation of mitochondrial dynamics. A detailed investigation into the potential role of PS1 in mitochondrial dynamics is warranted. In this study, we investigated the effect of PS1 fAD mutations on mitochondrial dynamics in neuroblastoma M17 cells and mouse primary neurons by confocal microscopy analysis. Compared with control M17 cells, M17 cells overexpressing PS1 fAD mutants displayed fragmented mitochondria and abnormal and uneven mitochondrial distribution with mitochondria accumulating around the perinuclear area while more remote cytoplasmic areas were not covered by mitochondria. Importantly, fibroblasts from fAD patients with PS1 mutations also demonstrated abnormal mitochondrial dynamics. Our further studies in primary neurons revealed that PS1 knockout (KO) neurons demonstrated significant changes in mitochondria morphology, distribution and movement which could be prevented by co-expression of wild-type PS1, but not fAD-causing PS1 mutant, suggesting that PS1 is involved in the regulation of mitochondrial dynamics which may be impaired by PS1 fAD mutations. Most importantly we found that PS1 physically interacted with DLP1, a key regulator of both mitochondrial fission and distribution. These studies suggest that fAD-associated PS1 mutants may cause impaired regulation of mitochondrial dynamics through specific interaction with DLP1 which causes mitochondrial dysfunction and redistribution which adversely affects neuronal functions in AD.